Value of Improved Lipid Control in Patients at High Risk for Adverse Cardiac Events

Reducing lipid levels in high-risk patients can significantly reduce disease burden and, depending on final negotiated prices, PCSK9 inhibitors can make an economic contribution to this goal.

ABSTRACT

Objectives:Lipid-lowering therapy (LLT) is suboptimally used in patients with hyperlipidemia in the 2 highest statin benefit groups (SBGs), as categorized by the American College of Cardiology and the American Heart Association. This study estimated the social value of reducing low-density lipoprotein cholesterol (LDL-C) levels by 50% for patients in SBGs 1 and 2 who have been treated with standard LLT but have not reached LDL-C goal, as well as the potential value of PCSK9 inhibitors for patients in these groups.

Study Design: Simulation model.

Methods: We used National Health and Nutrition Examination Surveys (NHANES) and US Census data to project the population of SBGs 1 and 2 in the time period 2015 to 2035. We used insurance claims data to estimate incidence rates of major adverse cardiac events (MACEs), and NHANES with National Vital Statistics data to estimate cardiovascular disease mortality rates. Using established associations between LDL-C and MACE risk, we estimated the value of reducing LDL-C levels by 50%. We incorporated results from a meta-analysis to estimate the value of PSCK9 inhibitors.

Results:Among those treated with LLT with LDL-C >70 mg/dL in SBGs 1 and 2, the cumulative value of reducing LDL-C levels by 50% would be $2.9 trillion from 2015 to 2035, resulting primarily from 1.6 million deaths averted. The cumulative value of PCSK9 inhibitors would range from $3.4 trillion to $5.1 trillion (1.9-2.8 million deaths averted), or $12,000 to $17,000 per patient-year of treatment.

Conclusions: Lowering LDL-C in high-risk patients with hyperlipidemia has enormous potential social value. For patients in these high-risk groups, PCSK9 inhibitors may have considerable net value depending on the final prices payers ultimately select.

Am J Manag Care. 2016;22(6):e199-e207

Take-Away Points

Before PCSK9 inhibitors even reached market, their costs to the healthcare system were the subject of much scrutiny. We estimated the social value of PCSK9 inhibitors to place their costs in context with the value they generate for patients and society.

Our study confirmed what we already knew: reducing lipid levels significantly in high-risk patients can have a considerable health impact.

Our study suggests that depending on the resulting confirmation of current estimates of effectiveness, PCSK9 inhibitors can provide considerable value when appropriately targeted, even at currently negotiated prices.

We also show that estimates of the likely budget impact are considerably off the mark when realistic uptake patterns are applied.

Cardiovascular disease (CVD) remains the leading cause of death, disability, and medical costs in the United States. Nearly 1 in 3 Americans dies of heart disease or stroke, and the annual cost of CVD in the United States exceeds $600 billion.1 Elevated low-density lipoprotein cholesterol (LDL-C) has been associated with increased risk for CVD events and death.2-8 Historically, statins have served as first-line lipid-lowering therapy (LLT) for LDL-C reduction, although recent guidelines have questioned the role of specific LDL-C goals in the primary and secondary prevention of CVD events.3,9

Despite estimates of the costs of CVD in the United States, little is known about the economic value of reducing the hyperlipidemia burden among those at high risk for CVD who, despite use of standard LLT, do not achieve conventional LDL-C goals (eg, ≤70 mg/dL). The American College of Cardiology (ACC) and American Heart Association (AHA) classify patients as being in the highest-risk statin benefit groups (SBGs) with established atherosclerotic CVD (ASCVD) (SBG 1), LDL-C levels >190 mg/dL (SBG 2), and diabetes (SBG 3).3 Previous research estimated that up to 75% of high-risk patients treated with statins fail to achieve LDL-C of ≤70 mg/dL.10 High CVD event rates in this population, coupled with a substantial proportion of patients not at conventional LDL-C goals, suggest potentially large economic value from reducing the burden of hyperlipidemia. Previously, eliminating deaths resulting from CVD has been estimated to be worth nearly $50 trillion in economic value.11 For those initiating statin therapy between 1997 and 2008 alone, the value of averted deaths and CVD events may exceed $1 trillion.12

Members of a novel class of therapies called PCSK9 inhibitors have recently been approved for treatment of hyperlipidemia in patients in SBGs 1 and 2 who do not achieve LDL-C of ≤70 mg/dL despite receiving maximally tolerated LLT. In phase 2 and 3 trials, PCSK9 inhibitors have been shown to reduce LDL-C by between 50% and 77%, on average.13 Preliminary clinical outcomes from these studies suggest that PCSK9 inhibitors may reduce rates of major adverse cardiac events (MACEs) by up to 50%.13 Based on these findings, the FDA approved alirocumab and evolocumab for use in adults with heterozygous familial hypercholesterolemia or ASCVD, who require additional LDL-C reduction.14 Amidst these developments, payers and policy makers have expressed concern that PCSK9 inhibitors’ costs—announced at $14,100 and $14,600 annually for evolocumab and alirocumab, respectively—will dramatically increase healthcare spending.15,16

In this study, we estimated the economic value to the United States over the next 20 years (2015-2035) of reducing hyperlipidemia burden among those at high risk for MACEs (SBGs 1 and 2) who have not achieved conventional LDL-C goals despite use of standard LLT therapy. As a case study, we estimated the value to the United States of using PCSK9 inhibitors in these patients who are currently on LLT but have not achieved an LDL-C of ≤70 mg/dL.

METHODS

Overview of Approach

Our study had 2 objectives: first, we sought to quantify the clinical and economic values of reducing the burden of hyperlipidemia among patients in the United States at high risk for MACEs or CVD mortality who have been treated with standard LLT but have not achieved conventional LDL-C goals. Second, we sought to project the clinical and economic value of PCSK9 inhibitors in patients at particularly high risk of MACEs or CVD mortality who may be eligible for treatment with these agents—those in SBGs 1 and 2—who have been treated with standard LLT but have not achieved conventional LDL-C goals. We defined conventional LDL-C goals to be ≤70 mg/dL and analyzed the sensitivity to a higher threshold of ≤100 mg/dL.

We used the 2011 to 2012 National Health and Nutrition Examination Study (NHANES)17 to first estimate the proportion of the US adult population (nonpregnant adults 18 years or older) in SBGs 1 and 2, as outlined by ACC and AHA guidelines3 (see eAppendix Tables 1 and 2 [eAppendices available at www.ajmc.com]).3 We then divided each of these groups into 3 risk subgroups based on their use of, and LDL-C response to, LLT: subgroup A—patients on LLT who have not successfully reduced LDL-C to ≤70 mg/dL (or ≤100 mg/dL, in sensitivity analyses); subgroup B—patients at goal LDL-C on LLT; and subgroup C—patients not on LLT.3,17 We used US Census projections to estimate the size of each these populations from 2015 to 2035.18 We used the Truven Marketscan insurance claims database to estimate the rates of nonfatal CVD events (ie, unstable angina, myocardial infarction, coronary arterial revascularization, and ischemic stroke) and a combination of the NHANES mortality files and National Vital Statistics Mortality Report (2012) to estimate mortality rates for each of these groups (see eAppendix Tables 3-5).17,19,20

With projected prevalence of patients not at goal LDL-C despite being on LLT (or who are intolerant to statins), we estimated the number of CVD-related deaths and MACEs averted for subgroup A in the time period 2015 to 2035 if LDL-C levels were hypothetically reduced by 50%, as suggested by the ACC and AHA.3 To estimate the effects of LDL-C reductions, we used the quantitative relationship between LDL-C and relative risk of CVD events and mortality from the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis.9,13 We then quantified the economic value to the United States of averted CVD-related deaths and MACEs using standard health economic valuation approaches.12,21

We simulated the effects of PCSK9 inhibitor use for SBGs 1 and 2 in subgroup A patients. We projected the number of CVD-related deaths and MACEs averted in the time period 2015 to 2035, and the associated economic value if these patients were to receive PCSK9 inhibitors for further LDL-C reduction. We estimated the effects of PCSK9 inhibitors in 2 ways. First, we combined the LDL-C–lowering effects from PCSK9 inhibitor trials with the LDL-C relationship from the CTT Collaboration meta-analysis.9,13 Second, we used data on the effects of PCSK9 inhibitors on CVD-related death and MACEs from a meta-analysis of recent randomized controlled trials of these drugs.13 For a more detailed description of our methods for population and prevalence projections and event and mortality rate estimates, please see the eAppendix.

Across all PCSK9 inhibitor trials, the mean difference in LDL-C between those receiving LLT plus PCKS9 inhibitors compared with LLT alone was 59% (95% CI, 57%-61%). We used data from the CTT Collaboration meta-analysis (described in the eAppendix) to estimate the effect on clinical outcomes.9 Using this method, PCSK9 inhibitor use in SBG 1 was associated with a reduction in MACE risk ranging from 43% to 50%, and a 32% reduction in CVD mortality risk, assuming the same baseline LDL-C level as indicated above. In SBG 2, the mortality reduction was 45%. The estimated impact of PCSK9 inhibitors on clinical outcomes in this scenario was termed the “conservative efficacy” treatment scenario. Next, we modeled the impact of PCSK9 inhibitors on MACEs and CVD deaths by using direct outcomes data from a meta-analysis of PCSK9 trials.13 In the meta-analysis, PCSK9 inhibitor use was associated with a 50% relative risk reduction in rates of MACEs and CVD mortality. We termed this scenario the “high-efficacy” treatment scenario.

It should be noted that the studies in this meta-analysis were not weighted to detect differences in MACE outcomes, but for changes in LDL-C levels. Therefore, these results should be interpreted with caution.

We then modeled 3 uptake scenarios for PCSK9 inhibitors. In each scenario, PCSK9 inhibitor uptake began at 3% of the eligible population in 2015 (the eligible population included patients in SBGs 1 and 2 treated with standard LLT, but with LDL-C >70 mg/dL). Starting in 2016, uptake was assumed to increase linearly by 1%, 2%, or 3% for scenarios 1, 2, and 3, respectively, until 2023, when treatment uptake reached the maximum of 10% (scenario 1), 20% (scenario 2), or 30% (scenario 3) of the eligible population, and then remained constant through 2035.

Translating Clinical Outcomes Into Estimates of Economic Value

We estimated the economic value associated with averted CVD-related deaths and MACEs as follows. First, we identified the number of life-years gained by averting a single CVD-related death to be 14.9 additional life-years.22 As this number was taken from follow-up data based on a clinical trial, and clinical trials tend to exclude older age groups, we were concerned that this number may overstate the additional life-years after a CVD event. Therefore, we also undertook the same analysis using the mean life-years lost from an ischemic heart disease death from the US Burden of Disease Study23 (these results are shown in eAppendix Table A6). To value the gain in life-years, we used a value of $150,000 per life-year.21,24 The World Health Organization’s report on macroeconomics and health outlined an alternative approach to estimating the social value of lives saved due to healthcare interventions and concluded that healthcare interventions that save 1 life-year at a cost of less than 3 times the gross domestic product per capita (for a given country) are cost-effective.25

Second, we assessed the value of reducing CVD-related hospitalizations using a recent review of the incremental costs of these hospitalizations in the United States. We estimated total cost savings from averted CVD hospitalizations by multiplying these unit cost estimates by the number of events averted.26 The value of life-years gained and savings from reduced CVD hospitalizations were summed to estimate both the total value of reducing residual LDL-C by the ACC/AHA goal of 50%, and the value of PCSK9 inhibitors in SBGs 1 and 2 for each of the 3 uptake scenarios described above. Future costs and benefits were discounted at 3%, using 2015 as the base year.

RESULTS

We estimated that in 2015, 32 million individuals in the United States would fall into ACC/AHA SBGs 1 and 2. Of these, 17.1 million did not receive LLT, 11.8 million were treated with standard LLT but had LDL-C >70 mg/dL, and 6.1 million were treated with standard LLT but had LDL-C >100 mg/dL. We projected that these figures would increase to 21.4 million, 16 million, and 8.1 million individuals, respectively, by 2035, absent changes in LLT use (Table 1). In 2015, the largest SBG—SBG 1—was estimated to have 10.1 million individuals with LDL-C >70 mg/dL and 4.4 million with LDL-C >100 mg/dL despite having been treated with LLT. By 2035, these figures were projected to increase to 14.0 million and 6.1 million, respectively.

Value of Averted MACEs and CVD Deaths Associated With a Hypothetical 50% LDL-C Reduction in SBGs 1 and 2